Amino acid phenoxy ethers

ABSTRACT

Novel amino acid phenyl ethers are provided which exhibit activity for the treatment of immunological diseases, inflammation, obesity, hyperlipidemia, hypertension, neurological diseases and diabetes.

This application claims priority of U.S. patent application Ser. No.10/356,113, filed Sep. 21, 2004, and the benefit of the earlier filingdate of U.S. Provisional Application No. 60/440,772 filed Jan. 17, 2003,both of which are incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to novel amino acid phenyl ethers for thetreatment of immunological diseases, inflammation, obesity,hyperlipidemia, hypertension, neurological diseases and diabetes.

BACKGROUND OF THE INVENTION

The principal elements of the immune system are macrophages orantigen-presenting cells, T cells and B cells. The role of other immunecells such as NK cells, basophils, mast cells and dendritic cells areknown, but their role in primary immunologic disorders is uncertain.Macrophages are important mediators of both inflammation and providingthe necessary “help” for T cell stimulation and proliferation. Mostimportantly macrophages make IL 1, IL 12 and TNF-α all of which arepotent pro-inflammatory molecules and also provide help for T cells. Inaddition, activation of macrophages results in the induction of enzymes,such as cyclooxygenase II (COX-2), inducible nitric oxide synthase(iNOS) and production of free radicals capable of damaging normal cells.Many factors activate macrophages, including bacterial products,superantigens and interferon gamma (IFN γ). It is believed thatphosphotyrosine kinases (PTKs) and other undefined cellular kinases areinvolved in the activation process.

Cytokines are molecules secreted by immune cells that are important inmediating immune responses. Cytokine production may lead to thesecretion of other cytokines, altered cellular function, cell divisionor differentiation. Inflammation is the normal response to injury orinfection. However, in inflammatory diseases such as rheumatoidarthritis, pathologic inflammatory processes can lead to morbidity andmortality. The cytokine tumor necrosis factor-alpha (TNF-α) plays acentral role in the inflammatory response and has been targeted as apoint of intervention in inflammatory disease. TNF-α is a polypeptidehormone released by activated macrophages and other cells. At lowconcentrations, TNF-α participates in the protective inflammatoryresponse by activating leukocytes and promoting their migration toextravascular sites of inflammation (Moser et al., J Clin Invest,83:444-55,1989). At higher concentrations, TNF-α can act as a potentpyrogen and induce the production of other pro-inflammatory cytokines(Haworth et al., Eur J Immunol, 21:2575-79, 1991; Brennan et al.,Lancet, 2:244-7, 1989). TNF-α also stimulates the synthesis ofacute-phase proteins. In rheumatoid arthritis, a chronic and progressiveinflammatory disease affecting about 1% of the adult U.S. population,TNF-α mediates the cytokine cascade that leads to joint damage anddestruction (Arend et al., Arthritis Rheum, 38:151-60,1995). Inhibitorsof TNF-α, including soluble TNF receptors (etanercept) (Goldenberg, ClinTher, 21:75-87, 1999) and anti-TNF-α antibody (infliximab) (Luong etal., Ann Pharmacother, 34:743-60, 2000), have recently been approved bythe U.S. Food and Drug Administration (FDA) as agents for the treatmentof rheumatoid arthritis.

Elevated levels of TNF-α have also been implicated in many otherdisorders and disease conditions, including cachexia, septic shocksyndrome, osteoarthritis, inflammatory bowel disease such as Crohn'sdisease and ulcerative colitis etc.

Excessive production of IL-6 is implicated in several disease states, itis highly desirable to develop compounds that inhibit IL-6 secretion.

The cytokine IL-1β also participates in the inflammatory response. Itstimulates thymocyte proliferation, fibroblast growth factor activity,and the release of prostaglandin from synovial cells.

Elevated or unregulated levels of the cytokine IL-1β have beenassociated with a number of inflammatory diseases and other diseasestates, including but not limited to adult respiratory distresssyndrome, allergy, Alzheimer's disease etc.

Since overproduction of IL-1β is associated with numerous diseaseconditions, it is desirable to develop compounds that inhibit theproduction or activity of IL-1β.

It will be appreciated from the foregoing that, while there have beenextensive prior efforts to provide compounds for inhibiting, forexample, TNF-α, IL-1, IL-6, COX-2 or other agents considered responsiblefor immune response, inflammation or inflammatory diseases, e.g.arthritis, there still remains a need for new and improved compounds foreffectively treating or inhibiting such diseases.

There appears to be a correlation of TNF-α to adipogenesis (obesity) andother metabolic disorders such as diabetes mellitus. Although, in thepast two decades there has been an explosive increase in number ofpeople diagnosed with diabetes worldwide [Amos A., McCarty, D., Zimmet,P. (1997) Diabetic Med. 14, S1-S85; King, H., Aubert, R., Herman, W.(1998) Diabetes Care, 21, 1414-1431], there has been relatively littledevelopment of new therapeutics for the treatment of diabetes and itsassociated conditions [Moller, D. E. (2001) Nature 414, 821-827].Diabetes exists in two types: insulin dependent Type-I and non-Insulindependent (insulin-resistant) Type-II. Type-II insulin-resistantdiabetes mellitus accounts for 90-95% of all diabetes. This syndromicmetabolic disorder currently affects more than 150 million peopleworldwide and is projected to grow to 300 million by year 2005 [Amos,A., McCarty, D., Zimmet, P. (1997) Diabetic Med. 14, S1-S85; Kopelman,P. G. Hitaman, G. A. (1998) Lancet, 352, SIV5). The main force drivingthis increase in incidence of type II diabetes is an increase inobesity, the single most important contribution to the pathogenesis oftype II diabetes [Kopelman, P. G., Hitaman, G. A. (1998) Lancet, 352,SIV5].

At present, therapy for type II diabetes relies mainly on severalapproaches intended to reduce the hyperglycemia itself. These are:sulfonylureas and related insulin secretogens that are known to releasemore insulin from pancreatic β cells; metformin, that acts to reducehepatic glucose production; peroxisome proliferator-activated receptor(PPAR) agonists that enhances insulin action; a-glucosidase inhibitorsthat slow down absorption of glucose from the gut; and insulin itself,that suppresses glucose production and augments glucose utilization(summarized in table I below). All of these therapies have limitedefficacy, limited tolerability and significant mechanism-based sideeffects. Of particular concern is the tendency for most treatment toenhance body weight gain. Several current treatments for type IIdiabetes are associated with episodes of hypoglycemia, and few of theavailable therapies adequately address underlying defects such asobesity and a phenomenon known as insulin resistance. Among these oralmedications, sulfonylureas represent the oldest and widely used form oftreatment. Many patients who respond to sulfonylureas initially becomerefractory to the treatment over time (secondary failure). Besidesglucose level and obesity, type II diabetes is now linked with highlevel of triglycerides and cholesterol. Therefore, there is a need fornew classes of drugs addressing the underlying issue of metabolicdefects (increasingly known as Syndrome-X) such as obesity,hyperglycemia and hyperlipidemic conditions to address type II diabetesand its associated condition. TABLE 1 Current Therapeutic agents forType II Diabetes Drug class Delivery Molecular Target Site of ActionAdverse Events Insulin Intramuscular Insulin receptor Liver, Muscle, FatWeight gain Hypoglycemia Sulfonylureas Oral SU receptors Pancreatic βcells Weight gain (glibenclamide) K+/ATP channel Hypoglycemia(repaglinide) (nateglinide) Metformin Oral Unknown Liver (muscle) GIdisturbance (biguanides) Lactic acidosis α-Glucosidase Oralα-Glucosidase Intestine GI disturbance Inhibitors (Acarbose)PPAR-agonist Oral PPAR-gamma Fat, Muscle, Liver Weight gain(Rosiglitazone) Anaemia (Pioglitazone) Oedema

SUMMARY OF THE INVENTION

The present invention, relates to novel amino acid phenyl ethers offormula (I)

their derivatives, their analogs, their tautomeric forms, theirstereoisomers, their polymorphs, their pharmaceutically acceptablesalts, their pharmaceutically acceptable solvates, wherein — representsoptional double bond; Y represents oxygen, sulfur or NR, wherein Rrepresents hydrogen or alkyl; Z represents oxygen or sulfur; R₁, R₂, R₃and R₄ may be same or different and independently represent hydrogen,halogen, hydroxy, nitro, cyano, formyl, amino, alkyl, alkoxy group; Arepresents a bond or substituted or unsubstituted aryl, heterocyclyl orheteroaryl ring; X represents an alpha amino carboxylic acid or itsderivatives bonded to A or Y through its alpha side chain.

The present invention also relates to a process for the preparation ofthe above said novel compounds, their analogs, their derivatives, theirtautomeric forms, their stereoisomers, their polymorphs, theirpharmaceutically acceptable salts, pharmaceutically acceptable solvates,novel intermediates and pharmaceutical compositions containing them.Tautomeric forms are isomeric forms which exists in a state ofequilibrium capable of reacting according to either form. Stereoisomersinclude configurational isomers, such as cis- and trans-double bonds, aswell as optically active isomers having different spatial arrangementsof their atoms. Polymorphs are molecules which can crystallize in two ormore forms. Solvates are molecular or ionic complexes of molecules orions of solvent with those of a solute. An alpha-amino carboxylic acidincludes, but is not limited to, naturally-occurring amino acids. Thealpha side chain is a group, including hydrogen, covalently bonded tothe alpha carbon of an alpha-amino carboxylic acid. Analogs includethose compounds which differ by substitution of an oxygen, sulfur,nitrogen or carbon atom in place of such an atom. Analogs also includeatoms of the same family of the Periodic Table, such as F, Cl, Br, I,As. Derivatives include compounds resulting from routine functionalizingof atoms, such as, derivatives found by protecting amino or carboxylgroups by carboxylation or esterification, respectively.

The compounds of the present invention are effective in lowering bloodglucose, serum insulin, free fatty acids, cholesterol and triglyceridelevels and are useful in the treatment and/or prophylaxis of diabetes.The compounds of the present invention are effective in treatment ofobesity, inflammation, autoimmune diseases such as such as multiplesclerosis and rheumatoid arthritis. Surprisingly, these compoundsincrease the leptin level and have no liver toxicity.

Furthermore, the compounds of the present invention are useful for thetreatment of disorders associated with insulin resistance, such aspolycystic ovary syndrome, as well as hyperlipidemia, coronary arterydisease and peripheral vascular disease, and for the treatment ofinflammation and immunological diseases, particularly those mediated bycytokines such as TNF-α, IL-1, IL-6, IL-1β and cyclooxygenase such asCOX-2.

BRIEF DESCRIPTION OF FIGURES

FIG. 1 shows that the compounds in Example 1 lower pro-inflammatorycytokines in human macrophage cells.

FIG. 2 shows efficacy of compound 2 in Example 1 in an animal model ofinflammation.

FIG. 3 shows efficacy of compounds 1 and 2 in Example 1 in an animalmodel of autoimmunity.

FIG. 4 represents schematic illustration of various cytokines and theirrole in management of a number of inflammatory and autoimmune diseases.

FIG. 5 is a schematic illustration of how TNFα is linked to variousmetabolic disorders besides its inflammatory and autoimmune properties.

FIG. 6 shows the blood glucose lowering effect of compound in Example 1in ob/ob and db/db mice.

FIG. 7 shows the effect of compounds 1 and 2 in Example 1 in weight gainreduction in an animal model of obesity.

FIG. 8 shows the effect of compound2 in Example 1 an insulin sensitizingand lipid lowering activity.

FIG. 9 shows the effect of lipid accumulation in human preadipocyteswhen treated with various dosages of a compound of the inventioncompared to rosiglitazone.

DETAILED DESCRIPTION OF THE INVENTION

In an embodiment of the present invention, the groups represented by R₁,R₂, R₃ and R₄ are selected from hydrogen, halogen such as fluorine,chlorine, bromine or iodine; hydroxy, nitro, cyano, formyl, amino,linear or branched, substituted or unsubstituted (C₁-C₁₂)alkyl groupsuch as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl,pentyl, hexyl, octyl, nonyl and the like; substituted or unsubstituted(C₁-C₁₂)alkoxy group such as methoxy, ethoxy, propoxy, butoxy and thelike.

In an embodiment of the present invention, the group represented by A isselected from aryl such as phenyl, naphthyl, and the like; heteroarylring such as pyridyl, pyrrolyl, thiazolyl, indolyl, imidazolyl, furyland the like; heterocyclyl ring such as piperzine, morpholine,piperidine, pyrrolidine and the like. The group A may be mono, di or trisubstituted and the substituents are selected from halogen, hydroxy,nitro, cyano, formyl, amino, alkyl, haloalkyl, alkoxy, haloalkoxy andthe like.

In an embodiment of the present invention, the amino acid and side chainrepresented by X, X-A or X-A-Y is selected from alanine, glycine,arginine, asparagine, cysteine, glutamic acid, glutamine, histidine,isoleucine, leucine, lysine, methionine, ornithine, proline, serine,threonine, tryptophan, tyrosine and the like, which may be substitutedor unsubstituted and their derivatives such as ester and amides ofcarboxylic acid. The preferred substituents are selected from halogen,alkyl, alkoxy, aryl, heteroaryl, amino and the like.

The amino acid X-A-Y preferably represents substituted or unsubstitutedarginine, asparagine, cysteine, glutamine, histidine, lysine,methionine, ornithine, proline, serine, threonine, tryptophan, tyrosineand their derivatives. The group X-A also preferably represents alanine,glycine, isoleucine, leucine and their derivatives. In anotherembodiment A represents a substituted or unsubstituted alkyl,heterocyclyl or heteroaryl ring.

In another embodiment, Z is sulfur and Y is oxygen. Preferably, R,through R₄ are hydrogen.

Pharmaceutically acceptable salts forming part of this invention includebase addition salts such as alkali metal salts like Li, Na, and K salts,alkaline earth metal salts like Ca and Mg salts, salts of organic basessuch as lysine, arginine, guanidine, diethanolamine, choline and thelike, ammonium or substituted ammonium salts. Salts may include acidaddition salts which are, sulphates, nitrates, phosphates, perchlorates,borates, hydrohalides, acetates, tartrates, maleates, citrates,succinates, palmoates, methanesulphonates, benzoates, salicylates,hydroxynaphthoates, benzenesulfonates, ascorbates, glycerophosphates,ketoglutarates and the like. Pharmaceutically acceptable solvates may behydrates or comprising other solvents of crystallization such asalcohols.

Preferably, the present invention relates to novel amino acid phenylethers of formula

their derivatives, their analogs, their tautomeric forms, theirstereoisomers, their polymorphs, their pharmaceutically acceptablesalts, their pharmaceutically acceptable solvates, wherein — representsoptional double bond; Y represents oxygen, sulfur or NR, wherein Rrepresents hydrogen or alkyl; Z represents oxygen or sulfur; R₁, R₂, R₃and R₄ may be same or different and independently represent hydrogen,halogen, hydroxy, nitro, cyano, formyl, amino, alkyl, or alkoxy; Arepresents substituted or unsubstituted aryl; X represents an alphaamino carboxylic acid or its derivatives bonded through its alpha sidechain to A.

More preferably, the present invention relates to novel amino acidphenyl ethers of formula (I)

their derivatives, their analogs, their tautomeric forms, theirstereoisomers, their polymorphs, their pharmaceutically acceptablesalts, their pharmaceutically acceptable solvates, wherein — representsoptional double bond; Y represents oxygen, sulfur or NR, wherein Rrepresents hydrogen or alkyl; Z represents oxygen or sulfur; R₁, R₂, R₃and R₄ may be same or different and independently represent hydrogen,halogen, hydroxy, nitro, cyano, formyl, amino, alkyl, or alkoxy; Arepresents substituted or unsubstituted phenyl; X represents alanine orits derivatives bonded to A through its alpha methyl group.

Particularly useful compounds according to the invention include:

-   5-[4-(4-(2-Amino-2-carboxyethyl)phenoxy)benzilidene]thiazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-methoxycarbonylethyl)phenoxy)benzilidene]thiazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-carboxyethyl)phenoxy)benzyl]thiazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-methoxycarbonylethyl)phenoxy)benzyl]thiazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-carboxyethyl)phenoxy)benzilidene]oxazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-methoxycarbonylethyl)phenoxy)benzilidene]oxazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-carboxyethyl)phenoxy)benzyl]oxazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-methoxycarbonylethyl)phenoxy)benzyl]oxazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-carboxyethyl)phenoxy)-2,6-difluorobenzilidene]oxazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-methoxycarbonylethyl)phenoxy)-2,6-difluorobenzilidene]oxazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-carboxyethyl)phenoxy)-2,6-difluorobenzyl]oxazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-methoxycarbonylethyl)phenoxy)-2,6-difluorobenzyl]oxazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-carboxyethyl)phenoxy)-2,6-difluorobenzilidene]thiazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-methoxycarbonylethyl)phenoxy)-2,6-difluorobenzilidene]thiazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-carboxyethyl)phenoxy)-2,6-difluorobenzyl]thiazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-methoxycarbonylethyl)phenoxy)-2,6-difluorobenzyl]thiazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-carboxyethyl)phenoxy)-2,3-difluorobenzilidene]thiazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-methoxycarbonylethyl)phenoxy)-2,3-difluorobenzilidene]thiazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-carboxyethyl)phenoxy)-2,3-difluorobenzyl]thiazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-methoxycarbonylethyl)phenoxy)-2,3-difluorobenzyl]thiazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-carboxyethyl)phenoxy)-2,3-difluorobenzilidene]oxazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-methoxycarbonylethyl)phenoxy)-2,3-difluorobenzilidene]oxazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-carboxyethyl)phenoxy)-2,3-difluorobenzyl]oxazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-methoxycarbonylethyl)phenoxy)-2,3-difluorobenzyl]oxazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-carboxyethyl)phenoxy)-3-methylbenzilidene]oxazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-methoxycarbonylethyl)phenoxy)-3-methylbenzilidene]oxazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-carboxyethyl)phenoxy)-3-methylbenzyl]oxazolidin-2,4-dione    or its salts;-   5 -[4-(4-(2-Amino-2-methoxycarbonylethyl)phenoxy)-3    -methylbenzyl]oxazolidin-2,4-dione or its salts;-   5-[4-(4-(2-Amino-2-carboxyethyl)phenoxy)-3-methylbenzilidene]thiazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-methoxycarbonylethyl)phenoxy)-3-methylbenzilidene]thiazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-carboxyethyl)phenoxy)-3-methylbenzyl]thiazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-methoxycarbonylethyl)phenoxy)-3-methylbenzyl]thiazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-carboxyethyl)phenoxy)-3-nitrobenzilidene]thiazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-methoxycarbonylethyl)phenoxy)-3-nitrobenzilidene]thiazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-carboxyethyl)phenoxy)-3-nitrobenzyl]thiazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-methoxycarbonylethyl)phenoxy)-3-nitrobenzyl]thiazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-carboxyethyl)phenoxy)-3-nitrobenzilidene]oxazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-methoxycarbonylethyl)phenoxy)-3-nitrobenzilidene]oxazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-carboxyethyl)phenoxy)-3-nitrobenzyl]oxazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-methoxycarbonylethyl)phenoxy)-3-nitrobenzyl]oxazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-carboxyethyl)phenoxy)-3-aminobenzilidene]thiazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-methoxycarbonylethyl)phenoxy)-3-aminobenzilidene]thiazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-carboxyethyl)phenoxy)-3-aminobenzyl]thiazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-methoxycarbonylethyl)phenoxy)-3-aminobenzyl]thiazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-carboxyethyl)phenoxy)-3-aminobenzilidene]oxazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-methoxycarbonylethyl)phenoxy)-3-aminobenzilidene]oxazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-carboxyethyl)phenoxy)-3-aminobenzyl]oxazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-methoxycarbonylethyl)phenoxy)-3-aminobenzyl]oxazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-carboxyethyl)phenoxy)-2-fluorobenzilidene]thiazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-methoxycarbonylethyl)phenoxy)-2-fluorobenzilidene]thiazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-carboxyethyl)phenoxy)-2-fluorobenzyl]thiazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-methoxycarbonylethyl)phenoxy)-2-fluorobenzyl]thiazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-carboxyethyl)phenoxy)-2-fluorobenzilidene]oxazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-methoxycarbonylethyl)phenoxy)-2-fluorobenzilidene]oxazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-carboxyethyl)phenoxy)-2-fluorobenzyl]oxazolidin-2,4-dione    or its salts;-   5    -[4-(4-(2-Amino-2-methoxycarbonylethyl)phenoxy)-2-fluorobenzyl]oxazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-carboxyethyl)phenoxy)-3-fluorobenzilidene]thiazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-methoxycarbonylethyl)phenoxy)-3-fluorobenzilidene]thiazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-carboxyethyl)phenoxy)-3-fluorobenzyl]thiazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-methoxycarbonylethyl)phenoxy)-3-fluorobenzyl]thiazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-carboxyethyl)phenoxy)-3-fluorobenzilidene]oxazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-methoxycarbonylethyl)phenoxy)-3-fluorobenzilidene]oxazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-carboxyethyl)phenoxy)-3-fluorobenzyl]oxazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-methoxycarbonylethyl)phenoxy)-3-fluorobenzyl]oxazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-carboxyethyl)phenoxy)-2-trifluoromethylbenzilidene]thiazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-methoxycarbonylethyl)phenoxy)-2-trifluoromethylbenzilidene]thiazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-carboxyethyl)phenoxy)-2-trifluoromethylbenzyl]thiazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-methoxycarbonylethyl)phenoxy)-2-trifluoromethylbenzyl]thiazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-carboxyethyl)phenoxy)-2-trifluoromethylbenzilidene]oxazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-methoxycarbonylethyl)phenoxy)-2-trifluoromethylbenzilidene]oxazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-carboxyethyl)phenoxy)-2-trifluoromethylbenzyl]oxazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-methoxycarbonylethyl)phenoxy)-2-trifluoromethylbenzyl]oxazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-carboxyethyl)phenoxy)-3-trifluoromethylbenzilidene]thiazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-methoxycarbonylethyl)phenoxy)-3-trifluoromethylbenzilidene]thiazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-carboxyethyl)phenoxy)-3-trifluoromethylbenzyl]thiazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-methoxycarbonylethyl)phenoxy)-3-trifluoromethylbenzyl]thiazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-carboxyethyl)phenoxy)-3-trifluoromethylbenzilidene]oxazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-methoxycarbonylethyl)phenoxy)-3-trifluoromethylbenzilidene]oxazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-carboxyethyl)phenoxy)-3-trifluoromethylbenzyl]oxazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-methoxycarbonylethyl)phenoxy)-3-trifluoromethylbenzyl]oxazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-carboxyethyl)-2,6-difluorophenoxy)benzilidene]oxazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-methoxycarbonylethyl)-2,6-difluorophenoxy)benzilidene]oxazolidin-2,4-dione    or its salts-   5-[4-(4-(2-Amino-2-carboxyethyl)-2,6-difluorophenoxy)benzyl]oxazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-methoxycarbonylethyl)-2,6-difluorophenoxy)benzyl]oxazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-carboxyethyl)-2,6-difluorophenoxy)benzilidene]thiazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-methoxycarbonylethyl)-2,6-difluorophenoxy)benzilidene]thiazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-carboxyethyl)-2,6-difluorophenoxy)benzyl]thiazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-methoxycarbonylethyl)-2,6-difluorophenoxy)benzyl]thiazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-carboxyethyl)-2,3-difluorophenoxy)benzilidene]thiazolidin-2,4-dione    or its salts-   5-[4-(4-(2-Amino-2-methoxycarbonylethyl)-2,3-difluorophenoxy)benzilidene]thiazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-carboxyethyl)-2,3-difluorophenoxy)benzyl]thiazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-methoxycarbonylethyl)-2,3-difluorophenoxy)benzyl]thiazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-carboxyethyl)-2,3-difluorophenoxy)benzilidene]oxazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-methoxycarbonylethyl)-2,3    -difluorophenoxy)benzilidene]-oxazolidin-2,4-dione or its salts;-   5-[4-(4-(2-Amino-2-carboxyethyl)-2,3-difluorophenoxy)benzyl]oxazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-methoxycarbonylethyl)-2,3-difluorophenoxy)benzyl]oxazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-carboxyethyl)-3-methylphenoxy)benzilidene]oxazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-methoxycarbonylethyl)-3-methylphenoxy)benzilidene]oxazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-carboxyethyl)-3-methylphenoxy)benzyl]oxazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-methoxycarbonylethyl)-3-methylphenoxy)benzyl]oxazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-carboxyethyl)-3-methylphenoxy)benzilidene]thiazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-methoxycarbonylethyl)-3-methylphenoxy)benzilidene]thiazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-carboxyethyl)-3-methylphenoxy)benzyl]thiazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-methoxycarbonylethyl)-3-methylphenoxy)benzyl]thiazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-carboxyethyl)-3-nitrophenoxy)benzilidene]thiazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-methoxycarbonylethyl)-3-nitrophenoxy)benzilidene]thiazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-carboxyethyl)-3-nitrophenoxy)benzyl]thiazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-methoxycarbonylethyl)-3-nitrophenoxy)benzyl]thiazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-carboxyethyl)-3-nitrophenoxy)benzilidene]oxazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-methoxycarbonylethyl)-3-nitrophenoxy)benzilidene]oxazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-carboxyethyl)-3-nitrophenoxy)benzyl]oxazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-methoxycarbonylethyl)-3-nitrophenoxy)benzyl]oxazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-carboxyethyl)-3-aminophenoxy)benzilidene]thiazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-methoxycarbonylethyl)-3-aminophenoxy)benzilidene]thiazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-carboxyethyl)-3-aminophenoxy)benzyl]thiazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-methoxycarbonylethyl)-3    -aminophenoxy)benzyl]thiazolidin-2,4-dione or its salts;-   5-[4-(4-(2-Amino-2-carboxyethyl)-3-aminophenoxy)benzilidene]oxazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-methoxycarbonylethyl)-3-aminophenoxy)benzilidene]oxazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-carboxyethyl)-3-aminophenoxy)benzyl]oxazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-methoxycarbonylethyl)-3-aminophenoxy)benzyl]oxazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-carboxyethyl)-2-fluorophenoxy)benzilidene]thiazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-methoxycarbonylethyl)-2-fluorophenoxy)benzilidene]thiazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-carboxyethyl)-2-fluorophenoxy)benzyl]thiazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-methoxycarbonylethyl)-2-fluorophenoxy)benzyl]thiazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-carboxyethyl)-2-fluorophenoxy)benzilidene]oxazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-methoxycarbonylethyl)-2-fluorophenoxy)benzilidene]oxazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-carboxyethyl)-2-fluorophenoxy)benzyl]oxazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-methoxycarbonylethyl)-2-fluorophenoxy)benzyl]oxazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-carboxyethyl)-3-fluorophenoxy)benzilidene]thiazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-methoxycarbonylethyl)-3-fluorophenoxy)benzilidene]thiazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-carboxyethyl)-3-fluorophenoxy)benzyl]thiazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-methoxycarbonylethyl)-3-fluorophenoxy)benzyl]thiazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-carboxyethyl)-3-fluorophenoxy)benzilidene]oxazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-methoxycarbonylethyl)-3-fluorophenoxy)benzilidene]oxazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-carboxyethyl)-3-fluorophenoxy)benzyl]oxazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-methoxycarbonylethyl)-3-fluorophenoxy)benzyl]oxazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-carboxyethyl)-2-trifluoromethylphenoxy)benzilidene]thiazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-methoxycarbonylethyl)-2-trifluoromethylphenoxy)benzilidene]thiazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-carboxyethyl)-2-trifluoromethylphenoxy)benzyl]thiazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-methoxycarbonylethyl)-2-trifluoromethylphenoxy)benzyl]thiazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-carboxyethyl)-2-trifluoromethylphenoxy)benzilidene]oxazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-methoxycarbonylethyl)-2-trifluoromethylphenoxy)benzilidene]oxazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-carboxyethyl)-2-trifluoromethylphenoxy)benzyl]oxazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-methoxycarbonylethyl)-2-trifluoromethylphenoxy)benzyl]oxazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-carboxyethyl)-3-trifluoromethylphenoxy)benzilidene]thiazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-methoxycarbonylethyl)-3-trifluoromethylphenoxy)benzilidene]thiazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-carboxyethyl)-3-trifluoromethylphenoxy)benzyl]thiazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-methoxycarbonylethyl)-3-trifluoromethylphenoxy)benzyl]thiazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-carboxyethyl)-3-trifluoromethylphenoxy)benzilidene]oxazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-methoxycarbonylethyl)-3-trifluoromethylphenoxy)benzilidene]oxazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-carboxyethyl)-3-trifluoromethylphenoxy)benzyl]oxazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-Amino-2-methoxycarbonylethyl)-3-trifluoromethylphenoxy)benzyl]oxazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-t-butoxycarbonylamino-2-methoxycarbonylethyl)phenoxy)benzilidene]thiazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-t-butoxycarbonylamino-2-methoxycarbonylethyl)phenoxy)benzyl]thiazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-t-butoxycarbonylamino-2-methoxycarbonylethyl)phenoxy)benzilidene]oxazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-t-butoxycarbonylamino-2-methoxycarbonylethyl)phenoxy)benzyl]oxazolidin-2,4-dione    or its salts.-   5-[4-(4-(2-t-butoxycarbonylamino-2-carboxyethyl)phenoxy)    benzilidene]thiazolidin-2,4-dione or its salts;-   5-[4-(4-(2-t-butoxycarbonylamino-2-carboxyethyl)phenoxy)benzyl]thiazolidin-2,4-dione    or its salts;-   5-[4-(4-(2-t-butoxycarbonylamino-2-carboxyethyl)phenoxy)benzilidene]oxazolidin-2,4-dione    or its salts and

5-[4-(4-(2-t-butoxycarbonylamino-2-carboxyethyl)phenoxy)benzyl]oxazolidin-2,4-dioneor its salts.

Compd No. X A Y R₂, R₃ R₄ Z  1

O H, H H S  2

O H, H H S  3

O H, H 2H S  4

O H, H 2H S  5

O H, H H O  6

O H, H H O  7

O H, H 2H O  8

O H, H 2H O  9

O 2-F, 6-F H O  10

O 2-F, 6-F H O  11

O 2-F, 6-F 2H O  12

O 2-F, 6-F 2H O  13

O 2-F, 6-F H S  14

O 2-F, 6-F H S  15

O 2-F, 6-F 2H S  16

O 2-F, 6-F 2H S  17

O 2-F, 6-F 2H S  18

O 2-F, 3-F H S  19

O 2-F, 3-F 2H S  20

O 2-F, 3-F 2H S  21

O 2-F, 3-F H O  22

O 2-F, 3-F H O  23

O 2-F, 3-F 2H O  24

O 2-F, 3-F 2H O  25

O 3-Me H O  26

O 3-Me H O  27

O 3-Me 2H O  28

O 3-Me 2H O  29

O 3-Me H S  30

O 3-Me H S  31

O 3-Me 2H S  32

O 3-Me 2H S  33

O 3-NO₂ H S  34

O 3-NO₂ H S  35

O 3-NO₂ 2H S  36

O 3-NO₂ 2H S  37

O 3-NO₂ H O  38

O 3-NO₂ H O  39

O 3-NO₂ 2H O  40

O 3-NO₂ 2H O  41

O 3-NH₂ H S  42

O 3-NH₂ H S  43

O 3-NH₂ 2H S  44

O 3-NH₂ 2H S  45

O 3-NH₂ H O  46

O 3-NH₂ H O  47

O 3-NH₂ 2H O  48

O 3-NH₂ 2H O  49

O 2-F H S  50

O 2-F H S  51

O 2-F 2H S  52

O 2-F 2H S  53

O 2-F H O  54

O 2-F H O  55

O 2-F 2H O  56

O 2-F 2H O  57

O 3-F H S  58

O 3-F H S  59

O 3-F 2H S  60

O 3-F 2H S  61

O 3-F H O  62

O 3-F H O  63

O 3-F 2H O  64

O 3-F 2H O  65

O 2-CF₃ H S  66

O 2-CF₃ H S  67

O 2-CF₃ 2H S  68

O 2-CF₃ 2H S  69

O 2-CF₃ H O  70

O 2-CF₃ H O  71

O 2-CF₃ 2H O  72

O 2-CF₃ 2H O  73

O 3-CF₃ H S  74

O 3-CF₃ H S  75

O 3-CF₃ 2H S  76

O 3-CF₃ 2H S  77

O 3-CF₃ H O  78

O 3-CF₃ H O  79

O 3-CF₃ 2H O  80

O 3-CF₃ 2H O  81

O H, H H O  82

O H, H H O  83

O H, H 2H O  84

O H, H 2H O  85

O H, H H S  86

O H, H H S  87

O H, H 2H S  88

O H, H 2H S  89

O H, H H S  90

O H, H H S  91

O H, H 2H S  92

O H, H 2H S  93

O H, H H O  94

O H, H H O  95

O H, H 2H O  96

O H, H 2H O  97

O H, H H O  98

O H, H H O  99

O H, H 2H O 100

O H, H 2H O 101

O H, H H S 102

O H, H H S 103

O H, H 2H S 104

O H, H 2H S 105

O H, H H O 106

O H, H H O 107

O H, H 2H O 108

O H, H 2H O 109

O H, H H S 110

O H, H H S 111

O H, H 2H S 112

O H, H 2H S 113

O H, H H S 114

O H, H H S 115

O H, H 2H S 116

O H, H 2H S 117

O H, H H O 118

O H, H H O 119

O H, H 2H O 120

O H, H 2H O 121

O H, H H S 122

O H, H H S 123

O H, H 2H S 124

O H, H 2H S 125

O H, H H O 126

O H, H H O 127

O H, H 2H O 128

O H, H 2H O 129

O H, H H S 130

O H, H H S 131

O H, H 2H S 132

O H, H 2H S 133

O H, H H O 134

O H, H H O 135

O H, H 2H O 136

O H, H 2H O 137

O H, H H S 138

O H, H H S 139

O H, H 2H S 140

O H, H 2H S 141

O H, H H O 142

O H, H H O 143

O H, H 2H O 144

O H, H 2H O 145

O H, H H S 146

O H, H H S 147

O H, H 2H S 148

O H, H 2H S 149

O H, H H O 150

O H, H H O 151

O H, H 2H O 152

O H, H 2H O 153

O H, H H S 154

O H, H H S 155

O H, H 2H S 156

O H, H 2H S 157

O H, H H O 158

O H, H H O 159

O H, H 2H O 160

O H, H 2H O 161

O H, H H S 162

O H, H 2H S 163

O H, H H O 164

O H, H 2H O 165

O H, H H S 166

O H, H 2H S 167

O H, H H O 168

O H, H 2H O

Preferred salts for the list of compounds above are hydrochloride,hydrobromide, sodium, potassium or magnesium.

According to another feature of the present invention, there is provideda process for the preparation of compounds of formula (I), wherein —represents a bond and all other symbols are as defined earlier, as shownin scheme-I

The reaction of compound of formula (IIIa) wherein X₁ represents aprotected alpha amino carboxylic acid group and all other symbols are asdefined earlier with the compound of formula (IIIb) wherein L representsa nucleophilic aromatic substitution leaving group, and all othersymbols are as defined earlier to produce a compound of formula (IIIc)may be carried out in the presence of solvents such as THF, DMF, DMSO,DME and the like or mixtures of solvents may be used. The reaction maybe carried out in an inert atmosphere which may be maintained by usinginert gases such as N₂, Ar or He. The reaction may be effected in thepresence of a base such as K₂CO₃, Na₂CO₃, NaH or mixtures thereof. Thereaction temperature may range from 20° C. to 150° C., preferably at atemperature in the range of 30° C. to 100° C. The duration of thereaction may range from 1 to 24 hours, preferably from 2 to 6 hours.

The conventional protecting groups used are those that can be easilyremoved and are selected from t-Boc, CBz, F-moc, etc.

The reaction of the compound of the general formula (IIIc) with2,4-thiazolidinedione or 2,4-oxazolidinedione to yield a compound offormula (IIId) may be carried out neat in the presence of sodium acetateor in the presence of a solvent such as benzene, toluene, methoxyethanolor mixtures thereof. The reaction temperature may range from 80° C. to180° C., when the reaction is carried out neat in the presence of sodiumacetate. Suitable catalyst such as piperidinium acetate or benzoate,sodium acetate or mixtures of catalysts may also be employed. Sodiumacetate can be used in the presence of solvent, but it is preferred thatsodium acetate is used neat. The water produced in the reaction may beremoved, for example, by using Dean Stark water separator or by usingwater absorbing agents like molecular sieves.

The deprotection of amino acid group of formula (IIId) to yield compoundof formula (I) may be carried out using acids such as HCl, sulfuricacid, acetic acid in the presence of solvents such as DCM, ethylacetate, water and the like or mixture thereof at a temperature in therange of −10° C. to 50° C.

In another embodiment of the present invention, the compounds of generalformula (I) wherein Z represents sulfur, — represents no bond can beprepared by reacting the compound of formula (IIIe)

wherein J is halogen atom, like chlorine, bromine or iodine and R₅ is alower alkyl group with thiourea followed by treatment with an acid.

The reaction of compound of general formula (IIIe) with thiourea iscarried out in the presence of alcoholic solvent such as methanol,ethanol, propanol, isobutanol, 2-methoxybutanol, etc or DMSO orsulfolane. The reaction may be conducted at a temperature in the rangebetween 20° C. and the reflux temperature of the solvent used. Basessuch as NaOAc, KOAc, NaOMe, NaOEt etc. can be used.

In yet another embodiment of the present invention, the compounds of thegeneral formula (I) wherein — represents a bond and all other symbolsare as defined earlier can also be prepared by reacting a compound offormula (IIIf)X-A-L   (IIIf)wherein L is a nucleophilic leaving such as halogen atom, like chlorine,bromine or iodine; methanesulfonate, trifluoromethanesulfonate,p-toluenesulfonate and the like with a compound of the formula (IIIg).

The reaction of compound of general formula (IIIf) with a compound ofgeneral formula (IIIg) to produce a compound of general formula (I) maybe carried out in the presence of solvents such as THF, DMF, DMSO, DMEand the like or mixtures thereof. The reaction may be carried out in aninert atmosphere which may be maintained by using inert gases such asN₂, Ar or He. The reaction may be effected in the presence of a basesuch as alkalis like sodium hydroxide or potassium hydroxide; alkalimetal carbonates like sodium carbonate or potassium carbonate; alkalimetal hydrides such as sodium hydride; organometallic bases like n-butyllithium; alkali metal amides like sodamide, or mixtures thereof.Multiple solvents and bases can be used. The amount of base may rangefrom 1 to 5 equivalents, preferably 1 to 3 equivalents. The reactiontemperature may be in the range of 0° C. to 120° C., preferably at atemperature in the range of 20° C. to 100° C. The duration of thereaction may range from 0.5 to 24 hours, preferably from 0.5 to 6 hrs.

In yet another embodiment of the present invention, the compounds of thegeneral formula (I) wherein — represents a bond and all other symbolsare as defined earlier can also be prepared by reacting a compound offormula (IIIh)X-A-OH   (IIIb)where A and X are as defined earlier with a compound of the formula(IIIg).

The reaction of compound of general formula (IIIh) with a compound ofgeneral formula (IIIg) to produce a compound of general formula (I) maybe carried out in the presence of solvents such as THF, DMF, DMSO, DMEand the like or mixtures thereof. The reaction may be carried out in aninert atmosphere which may be maintained by using inert gases such asN₂, Ar or He. The reaction may be effected in the presence of a basesuch as alkalis like sodium hydroxide or potassium hydroxide; alkalimetal carbonates like sodium carbonate or potassium carbonate; alkalimetal hydrides such as sodium hydride; organometallic bases like n-butyllithium; alkali metal amides like sodamide, or mixtures thereof.Multiple solvents and bases can be used. The amount of base may rangefrom 1 to 5 equivalents, preferably 1 to 3 equivalents. The reactiontemperature may be in the range of 0° C. to 120° C., preferably at atemperature in the range of 20° C. to 100° C. The duration of thereaction may range from 0.5 to 24 hours, preferably from 0.5 to 6 hrs.

In another embodiment of the present invention, there is provided aprocess for the preparation of compounds of formula (I), wherein —represents no bond by reducing compounds of formula (I) wherein —represents a bond and all other symbols are as defined earlier. Thereduction may be carried out in the presence of gaseous hydrogen and acatalyst such as Pd/C, Rh/C, Pt/C, Raney Nickel, and the like. Mixturesof catalysts may be used. The reaction may be conducted in the presenceof solvents such as dioxane, acetic acid, ethyl acetate and the like.Mixtures of solvents may be used. A pressure between atmosphericpressure to 100 psi may be employed. The catalyst may be 5-10% Pd/C andthe amount of catalyst used may range from 50-300% w/w. The reaction mayalso be carried out by employing metal solvent reduction such asmagnesium in methanol or sodium amalgam in methanol. The reaction mayalso be carried out with alkali metal borohydrides such as LiBH₄, NaBH₄,KBH₄ and the like in the presence of cobalt salt such as CoCl₂ andligands, preferably bidentated ligands such as 2,2′-bipyridyl,1,10-phenanthroline, bisoximes and the like.

In yet another embodiment of the present invention, there is provided anintermediate of formula (IIIc)

their derivatives, their analogs, their tautomeric forms, theirstereoisomers, their polymorphs, their pharmaceutically acceptablesalts, their pharmaceutically acceptable solvates, wherein Y representsoxygen, sulfur or NR, wherein R represents hydrogen or alkyl; R₁, R₂, R₃and R₄ may be same or different and independently represent hydrogen,halogen, hydroxy, nitro, cyano, formyl, amino, alkyl, or alkoxy; Arepresents substituted or unsubstituted aryl; X represents an alphaamino carboxylic acid or its derivatives bonded to A through its alphaside chain.

In yet another embodiment of the present invention, there is provided anintermediate of formula (IIIe)

their derivatives, their analogs, their tautomeric forms, theirstereoisomers, their polymorphs, their pharmaceutically acceptablesalts, their pharmaceutically acceptable solvates, wherein Y representsoxygen, sulfur or NR, wherein R represents hydrogen or alkyl; R₁, R₂, R₃and R₄ may be same or different and independently represent hydrogen,halogen, hydroxy, nitro, cyano, formyl, amino, alkyl, or alkoxy; Arepresents substituted or unsubstituted aryl; X represents an alphaamino carboxylic acid or its derivatives bonded to A through its alphaside chain; J represents halogen atom and R₅ represents lower alkylgroup.

It has been surprisingly found that, unlike other thiazolidine-compounds(TZD molecules), compounds of the invention exhibit no adipocytedifferentiation. It is also surprising that administration reduces bodyweight gain. Finally, compounds of the invention appear to have noaffinity for PPAR-g. These three features of the compounds are differentfrom known TZD molecules, which typically have adipocyte differentiationactivity, increase weight gain, and are PPAR-g agonists. Furthermore,compounds of the invention have anti-inflammation properties. Forexample, the compounds inhibit TNFα, IL-6 and IL1β.

The compounds according to the present invention may be combined with aphysiologically acceptable vehicle in a pharmaceutical composition. Theparticularly preferred form of composition is an orally administratedcapsule or solution in which the compound is delivered in water, saline,a phosphate buffer, or lyophilized powder in a form of tablets orcapsules which also includes various fillers and binders. The effectivedosages of compound in a composition will be selected by those ofordinary skill in the art and may be empirically determined.

The compounds of the present invention are useful for the treatment ofinflammation, autoimmune diseases such as multiple sclerosis, IBD,obesity, neurological diseases, hypertension, and diseases such asdiabetes characterized by the presence of elevated blood glucose levels,that is hyperglycemic disorders such as diabetes mellitus, includingboth Type I and Type II diabetes as well as other hyperglycemic relateddisorders such as hyperlipidemia, kidney related disorders, and thelike.

By “treatment,” it is meant that the compound is administered at leastto reduce inflammation, hypertension, obesity, blood lipid levels, bloodglucose levels or symptoms associated with autoimmune or neurologicaldisease or disorder from which the patient is suffering. The compound isadministered in an amount sufficient, for example, to reduce bloodglucose level to an acceptable range, wherein an acceptable range means±10%, usually ±8% and usually ±5% of the normal average blood glucoselevel for the subject. A variety of subjects may be treated with thecompounds such as livestock, valuable or rare animals, pets, as well ashumans. The compounds may be administered to the subject using aconvenient administration technique, including intravenous, intradermal,intramuscular, subcutaneous, oral administration and the like. However,the oral route of administration is particularly preferred. The dosagedelivered to the host will necessarily depend upon the route by whichthe compound is delivered, but generally ranges from 5 to 500 mg/70 kghuman body weight.

The invention is explained in detail in the examples given below whichare provided by way of illustration only and therefore should not beconstrued to limit the scope of the invention.

EXAMPLE 1 Preparation of5-[4-(4-(2-amino-2-methoxycarbonylethyl)phenoxy)benzyl]-thiazolidin-2,4-dionehydrochloride salt

Step (i) Preparation ofmethyl-2-[(t-butoxycarbonyl)amino]-3-[-(4-formylphenoxy)phenyl]propanoate

To a suspension of fresh sodium hydride (0.813 g, 33.9 mmol) in dry DMF(20 ml) under nitrogen atmosphere was added the solution ofmethyl-2-[(t-butoxycarbonyl)amino]-3-(4-hydroxyphenyl)propanoate (10 g,33.9 mmol) in DMF (20 ml) slowly. The mixture was stirred for 15minutes. 4-Fluorobenzaldehyde (4.20 g, 33.9 mmol) was added and themixture was heated to 80° C. After completion of the reaction, thesolvent was removed by high vacuum and the mixture was quenched withaddition of saturated aqueous ammonium chloride. The mixture wasextracted with ethyl acetate (3×50 ml). After washing with brine anddried on anhydrous sodium sulfate, the solvent was evaporated and theproduct was purified with flash column from eluent of hexanes: ethylether; 12/30 to 12/22 to afford the title compound as an oil (yield 11.5g, 85.0%).

¹H NMR (CDCl₃, 360 M Hz,): δ 9.92 (s, 1H), 7.83 (d, 2H), 7.19 (d, 2H),7.05 (d, 2H), 7.03(d, 2H), 4.60(t, 1H), 3.72(s, 3H), 3.09(d, 2H),1.42(s, 9H). The structure was confirmed by Mass Spec. Calculated (M+1)400.4; Measured 400.3.

Step (ii) Preparation of5-[4-(4-(2-t-butoxycarbonylamino-2-methoxycarbonylethyl)phenoxy)benzilidene]thiazolidin-2,4-dione

To a solution ofmethyl-2-[(t-butoxycarbonyl)amino]-3-[-(4-formylphenoxy)phenyl]propanoateobtained in step (i) above in anhydrous toluene (10 g, 25 mmol),2,4-thiazolidinedione (3.53 g, 30 mmol) was added followed by benzoicacid (0.46 g, 3.75 mmol) and piperidine (0.28 g, 3.25 mmol). Thesolution was heated to reflux at 145-155° C. with continuous removal ofwater using Dean-Stark apparatus for 5 hr. The solution was cooled to RTand the yellow solid was precipitated to afford the title compound(yield 11.9 g, 96%, purity 96.5% by HPLC, mp: 160-164° C.).

¹H NMR (CDCl₃, 360 M Hz,): 7.82(s, 1H), 7.47(d, 2H); 7.05(d, 2H),7.00(d, 2H); 6.75(d, 2H) 5.18(m, 1H), 4.54(M, 1H), 3.71(s, 3H); 3.02(m,2H), 3.00(m, 2H). 1.42(s, 9H). The structure was confirmed by Mass Spec.Calculated (M+1) 498.5; Measured 498.5.

Step (iii) Preparation5-[4-(4-(2-amino-2-methoxycarbonylethyl)phenoxy)benzilidene]thiazolidin-2,4-dione

A solution of5-[4-(4-(2-t-butoxycarbonylamino-2-methoxycarbonylethyl)phenoxy)benzilidene]thiazolidin-2,4-dione(2 g, 4.0 mmol) in DCM (100 ml) at 0° C. was bubbled with HC1 gas. Afterstirring for 1 hour, the yellow precipitate was filtered and 1.7 g (3.9mmol) of HC1-Tyr (C6H4-CH=TDZ)-OMe was collected with 97.5% yield, mp:187-190° C. The HPLC purity of product was 94.5%. Compound 1.

^(1H) NMR (D2O, 360 M Hz,): 7.46(s, NH, 1H); 7.24(d, 2H); 7.16(d, 2H);6.94(d, 2H); 6.78(d, 2H); 4.80 (s, NH3, 3H); 4.40(m, Cα-H, 1H); 3.80(s,OMe). The structure was confirmed by Mass Spec. Calculated (M+1) 501.5;Measured 501.5.

Step (iv) Preparation of5-[4-(4-(2-amino-2-methoxycarbonylethyl)phenoxy)benzyl]thiazolidin-2,4-dione

To a solution of5-[4-(4-(2-amino-2-methoxycarbonylethyl)phenoxy)benzilidene]thiazolidin-2,4-dione(0.7 g, 1.6 mmol) in methanol (20 ml) dry Pd/C (0.15 g) was added. Afterhydrogenating at 60 psi at 40° C. over night, the solution was filteredwith Celite and evaporated under reduced pressure to yieldquantitatively the title compound. This compound did not show melting inDSC but changes to black colour, in capillary and shrinks at 97-133° C.Compound 2.

The pharmaceutically acceptable salts may be prepared by reacting thecompound of formula (I) with 1 to 4 equivalents of a base such as sodiumhydroxide, sodium methoxide, sodium hydride, potassium t-butoxide,calcium hydroxide, magnesium hydroxide and the like, in solvents likeether, THF, methanol, t-butanol, dioxane, isopropanol, ethanol etc.Mixtures of solvents may be used. Organic bases like lysine, arginine,diethanolamine, choline, guanidine and their derivatives etc. may alsobe used. Alternatively, acid addition salts are prepared by treatmentwith acids such as hydrochloric acid, hydrobromic acid, nitric acid,sulfuric acid, phosphoric acid, p-toluenesulfonic acid, methanesulfonicacid, acetic acid, citric acid, maleic acid, salicylic acid,hydroxynaphthoic acid, ascorbic acid, palmitic acid, succinic acid,benzoic acid, benzene sulfonic acid, tartaric acid and the like insolvents like ethyl acetate, ether, alcohols, acetone, THF, dioxane etc.Mixture of solvents may also be used.

The present invention also provides a pharmaceutical composition,containing one or more of the compounds of the general formula (I) asdefined above, their tautomeric forms, their derivatives, theiranalogues, their stereoisomers, their polymorphs, their pharmaceuticallyacceptable salts, their pharmaceutically acceptable solvates incombination with the usual pharmaceutically employed carriers, diluentsand the like.

The pharmaceutical composition may be in the forms normally employed,such as tablets, capsules, powders, syrups, solutions, suspensions andthe like, may contain flavourants, sweeteners etc. in suitable solid orliquid carriers or diluents, or in suitable sterile media to forminjectable solutions or suspensions. Such compositions typically containfrom 1 to 25%, preferably 1 to 15% by weight of active compound, theremainder of the composition being pharmaceutically acceptable carriers,diluents, excipients or solvents.

Suitable pharmaceutically acceptable carriers include solid fillers ordiluents and sterile aqueous or organic solutions. The active compoundwill be present in such pharmaceutical compositions in the amountssufficient to provide the desired dosage in the range as describedabove. Thus, for oral administration, the compounds can be combined witha suitable solid or liquid carrier or diluent to form capsules, tablets,powders, syrups, solutions, suspensions and the like. The pharmaceuticalcompositions, may, if desired, contain additional components such asflavourants, sweeteners, excipients and the like. For parenteraladministration, the compounds can be combined with sterile aqueous ororganic media to form injectable solutions or suspensions. For example,solutions in sesame or peanut oil, aqueous propylene glycol and the likecan be used, as well as aqueous solutions of water-solublepharmaceutically-acceptable acid addition salts or alkali or alkalineearth metal salts of the compounds. The injectable solutions prepared inthis manner can then be, administered intravenously, intraperitoneally,subcutaneously, or intramuscularly, with intramuscular administrationbeing preferred in humans.

The pharmaceutical composition of the present invention are particularlyeffective in lowering blood glucose, serum insulin and triglyceridelevels in animal models of types II diabetes. The pharmaceuticalcompositions of the present invention are also effective in thetreatment of obesity, inflammation, autoimmune diseases. Furthermore,pharmaceutical composition of the present invention are useful for thetreatment of disorders associated with insulin resistance, such aspolycystic ovary syndrome, as well as hyperlipidemia, coronary arterydisease and peripheral vascular disease, and for the treatment ofinflammation and immunological diseases, particularly those mediated bycytokines such as TNF-α, IL-1, IL-6 and cyclooxygenase such as COX-2.

Protocols for Biological Testing

Compounds of the present invention have been tested for loweringinflammatory cytokines level, chemically-induced inflammation, obesityand blood glucose, in different models for their biological activity.The attached FIGS. 1-9 shows the activity profile of the representativecompound.

FIG. 1. Compounds 1 and 2 in Example 1 Inhibit Major Pro-InflammatoryCytokines in Human Monocyte Cells

Human THP-1 monocyte cells were cultured and incubated with twocompounds of example 1 at different concentrations. Cells were thenchallenged with lipopolysaccharides (LPS) at a concentration of (1microgram/ml) for 24 hours. Cell supernatants were then analyzed for thepresence of TNFα, IL1β and IL-6 cytokines by antibody directedenzyme-linked immunoassay. As shown in FIG. 1, the example compounds caninhibit the production of three major pro-infalmmatory cytokines in adose dependent manner. No significant change in cell viability wasobserved with incubation of cells in the presence of highestconcentration of the compound. These strongly indicate that compound ofexample 1 is highly effective in reducing the production ofpro-inflammatory cytokines.

FIG. 2. Compound 2 in Example 1 can Lower Carrageenan InducedInflammation in Rats.

Spegue-Dowley rats of average weight 250 g (6-7 weeks of age) wererandomized in three goups, and given 50 mg/kg oral dose of compound ofexample 1. Thirty minutes later carrageenan was administered in thesub-planter region of right hind paws. Control group received equalvolume of water without any compound. Paw volume was measured after 2and three hours. Dexamethasone at a concentration of 5 mg/kg was used asa positive control in this experiment. As shown in FIG. 2, the compoundof example 1 can substantially lower the inflammation induced bycarrageenan. At time 3 hours the effect of compound of example-1 was aseffective as dexamethasone (a known anti-inflammatory drug that acts viadifferent mechanism pathways).

FIG. 3. Compounds 1 and 2 in Example 1 prevent EAE in mice (MultipleSclerosis Model)

Multiple sclerosis (MS) is an autoimmune disease and is regulated bycytokine levels. In order to test the effect of example 1 in MS model,experimental allergic encepahalomyalitis (EAE) was induced in SJL/Jmice. EAE is an autoimmune inflammatory disease of the central nervoussystem (CNS). The disease shows many similarities with the human MS, andhence is used as a model to test the-potential efficacy of new drugsthat may have applicability in MS. EAE was induced by injecting spinalchord homogenate where animals were treated with example compounds. Theseverity of EAE was established by clinical scores of paralysis. Asshown in FIG. 3, the new compound treated group showed completeprevention of EAE. These results indicate utility of the examplecompounds for the treatment of MS and other neurological disorders.

FIG. 4. Schematic Representation of Cytokine Modulation and ImmuneDisorders.

Macrophage produces various cytokines upon stimulation by mitogens andother unknown factors. Few of theses key cytokines are known to beinvolved in various immunological disorders including a number ofautoimmune diseases.

FIG. 5. Direct and Indirect Linkage of TNFα in Metabolic Diseases.

It has been well established that TNFα plays a major role ininflammatory diseases and autoimmune disorders with treatments availablefor rheumatoid arthritis using antibody against TNFα. In addition, anumber of studies in recent years have predicted the possible role ofTNFα in adipose biology and metabolic disorders such as diabetes,obesity, hyperlipidemic and vascular complications. The schematicillustration reflects how the regulation of TNFα can have impact on anumber of metabolic diseases, that can provide different pathways fortreating these diseases.

FIG. 6. Compound 2 in Example 1 Substantially Improves Hyperglycemia inDiabetic Mice.

The hypoglycemic effect of the compound has been examined in twospontaneous animal models of diabetes (ob/ob and db/db mice). The ob/obmice lacks leptin gene and is also considered a typical model forobesity. The db/db mice have defective leptin receptor and showhyperglycemia with significant weight gain. The compound at a dose of 5,10 and 50 mg/kg body weight was given orally in these animals for aperiod of 15-21 days. Treatment of both ob/ob and db/db diabetic animalsresulted in significant improvement of hyperglycemic conditions. Resultsare essentially the same for compound 1.

FIG. 7. The Compounds 1 and 2 in Example 1 Reduce Body Weight Gain inanimal Model of Obesity.

The leptin knock-out mice (ob/ob) are considered a suitable model forobesity besides diabetes. In order to test the efficacy of thesecompounds towards obesity, ob/ob mice were treated with compound for 21days. As shown in FIG. 7, single dose daily treatment of ob/ob mice withcompound can result in 35% improvement in body weight gain, indicatingthe utility of these compounds for the treatment of obesity. Thisfinding is opposite from that using other thiazolidines, which typicallyincrease weight.

FIG. 8. The Compound 2 in Example 1 can Improve Insulin Resistance andLipid Homeostasis.

The leptin knock-out ob/ob mice is also considered a good model forinsulin resistance. Treatment of these animals with the compound 2lowered serum insulin concentration by >70%. Similarly, a 48% decreasein triglyceride level and >50% decrease in serum cholesterolconcentrations were observed in 15-day treatment study. These resultsindicate that the compounds have strong anti-lipidemic properties andcan improve the sensitivity of insulin.

In a separate study, surprisingly it was observed that these compoundsare non-adipogenic in contrast to other known thiazolidinediones and hasvery weak or no affinity towards peroxisome proliferator activatorreceptor-gamma (PPAR-γ). All of these biological findings suggest thecompounds have novel properties and work by a very different mechanismof action from PPAR-γ binding.

FIG. 9. Known PPAR-g Agonist Rosiglitazone is an Adipogenic Agent, ButCompound 2 is Not.

Human subcutaneous preadipocytes were cultured in 96 well plate inpresence of vehicle or different doses (0.01, 0.1, 1.0, and 10microMolar) of either rosiglitazone (BRL) or compound 2 (BLX) for 13days. Every 72 hours media were changed with fresh compound. As TNFinhibits adipogenesis process, it was kept as negative control of theexperiment where coincubation with rosiglitazone showed a significantreduction in adipogenesis compared to rosiglitazone alone. On day 13cells were fixed and lipid (triglycerides) accumulation was measured bystaining with Oil Red O and pictures were under the microscope. To havemore quantitative data, Oil Red O was extracted by adding isopropanoland measured spectrophotometrically at 540 nM (as shown in the bargraph). It can be seen that regardless of dosage, compound 2 did notcause accumulation of lipids. Rosiglitazone showed a dose dependentincrease in lipid production, which could be inhibited by addition ofTNFα.

1. A compound formula (I)

its derivatives, its analogs, its tautomeric forms, its stereoisomers,its polymorphs, its pharmaceutically acceptable salts, itspharmaceutically acceptable solvates, wherein — represents an optionaldouble bond; Y represents oxygen, sulfur or NR, wherein R representshydrogen or alkyl; Z represents oxygen or sulfur; R₁, R₂, R₃ and R₄ maybe same or different and independently represent hydrogen, halogen,hydroxy, nitro, cyano, formyl, amino, alkyl, or alkoxy; A represents abond or substituted or unsubstituted aryl, heterocyclyl or heteroarylring; X represents an alpha amino carboxylic acid or alpha aminocarboxylic acid derivative bonded to A or Y through its alpha sidechain.
 2. A compound of formula (I) according to claim 1, wherein theX-A-Y-represents an amino acid selected from the group consisting ofsubstituted or unsubstituted arginine, asparagine, cysteine, glutamine,histidine, lysine, methionine, ornithine, proline, serine, threonine,tryptophan, tyrosine and their derivatives.
 3. A compound according toclaim 1 wherein A represents a substituted or unsubstituted alkyl,heterocyclyl or heteroaryl ring.
 4. A compound according to claim 1wherein X-A- represents an amino acid selected from the group consistingof alanine, glycine, isoleucine and leucine and their derivatives.
 5. Acompound according to claim 1 wherein A represents a bond.
 6. A compoundaccording to claim 1 wherein Z is sulfur and Y is oxygen.
 7. A compoundaccording to claim 1 wherein R₁ through R₄ are hydrogen.
 8. A compoundaccording to claim 1 wherein the — double bond is present.
 9. A compoundaccording to any of claims 1 through 5 wherein the — double bond isabsent.
 10. A compound according to claim 2 wherein X-A-Y— comprisestyrosine.
 11. A compound according to claim 2 wherein X-A-Y comprises atyrosine derivative.
 12. A compound according to claim 11 wherein saidderivative comprises an alkyl ester of tyrosine.
 13. A compoundaccording to claim 12 wherein said ester is the methyl ester.
 14. Acompound according to claim 10 or 11 wherein R₁, R₂, R₃ and R₄ arehydrogen and Z is sulfur.
 15. A compound according to claim 14 whereinthe — double bond is present.
 16. A compound according to claim 14wherein the — double bond is absent.